16-alkyl pregnane derivatives and process for the preparation thereof



United States Patent 4 Claims. c1. zen-397.4

This invention relates to novel biologically active compounds of thepregnane series and to processes for the preparation thereof.

More particularly, the invention relates to the preparation of a groupof new 1 6a-alkyl-steroids of the pregnane series having the formula:

R =an alkyl group having 14 carbon atoms, R =hydrogen or an acylradical, R =a keto group, I-I(OH) or H(OAcyl), and C C =saturated orunsaturated.

wherein The alkyl group in 16-position is a saturated aliphatichydrocarbon radical having 1 to 4 carbon atoms, e.g. a methyl, ethyl,propyl, isopropyl or butyl radical.

The compounds according to the invention are of great importance onaccount of their progestational, particularly long-acting progestationalactivity, ovulation-inhibiting and pregnancy-maintaining properties.

The above compounds may be prepared from the corresponding A3-keto-l6a-alkyl-compounds of the pregnane series having in the 20-position a keto, hydroxyl or acyloxy group and wherein the bond betweenthe carbon atoms 6 and 7 may be saturated or unsaturated by reduction ofthe 3-keto group, if desired, together with the 20- keto group, afterwhich the thus obtained compounds may be esterified in the 3- and/or20-position.

As reducing agent may be used an alkalimetal aluminium hydride, e.g.lithium aluminium hydride, an alkalimetal borohydride, e.g., potassiumborohydride and sodium borohydride, an alkalimetal trialkoxy aluminiumhydride, e.g., lithium trimethoxy aluminium hydride, sodium triethoxyaluminium hydride and lithium .tri-t-butoxy aluminium hydride, analkalimetal trialkoxy borohydride, e.g., sodium trimethoxy borohydride,and further with aluminium alkoxydes, e.g., aluminium isopropoxyde.

Starting from a A*-, or A -3,ZO-diketo-compound the ZO-keto group may bereduced together with the 3-keto group but it is also possible to reduceonly the 3-keto group either by selective reduction of this group or byprotection of the 20-keto group.

The selective reduction takes place if the reduction is performed withan alkalimetal borohydride in the presence of a suitable organicsolvent, for example, tetrahydrofuran or isopropanol. In that case it isdesirable to perform the reduction with only a small excess of theborohydride used, usually 1.1 to 1.5 equivalents.

Alternatively, the ZO-keto group may be protected temporarily, e.g. byketalisation for example as the ethyl enedioxy lcetal and regenerationof this group by treatment with an acid after the reduction step.

The A -3-hydroxy or acyloxy-pregnadiene compounds according to theinvention may be prepared also by bromination of the corresponding A-3/3-acyloxyor 3,6-hydroxy compound followed by dehydrobromination toobtain the corresponding A -3-acy1oxyor 3-hydroxy steroid.

The thus obtained A -3B-hydroxy 16a-alkyl compounds having in20-position a keto group or a ZOocor 20,8-hydroxyl group may beesterified in the 3 and/ or 20-position.

The esterification of the 3 3-hy droxyl group and the 200; orZOB-hydroxyl groups may be performed with an inorganic acid such asphosphoric acid, or sulphuric acid, or an aliphatic, aromatic oraraliphatic carboxylic acid, preferably with 118 carbon atoms, such asacetic acid, propionic acid, trimethyl acetic acid, valeric acid,caproic acid, oenanthic acid, caprylic acid, capric acid, lauric acid,undecylic acid, oleic acid, linolenic acid, palmitic acid, suocinicacid, cyclopentyl acetic acid, ,B-phenylpropionic acid, cyclohexylbutyric acid and tartaric acid.

3fl-monoesters may be prepared by esterification of theBfl-hydroxy-ZO-ketone, after which the 20-keto group may be reduced witha suitable reducing agent such as de-' scribed before.

20-monoesters can be prepared by suitable alkalimetal borohydride oraluminium hydride reduction of :the corresponding esters of therespective 3-keto-16a-alkyl20- hydroxy compounds. By furtheresterification of these 3-, and 20-rnonoesters using a different acid ora functional derivative thereof mixed diesters are obtained.

The process is illustrated by the following examples.

EXAMPLE I A solution of 16a-ethyl pregnenolone acetate (30 g.) inbenzene (1050 cc.) was treated with ethylene glycol cc.) and2,4-dinitrobenzenesulphonic acid (1 g.) and the solution refluxedvigorously for 65 hours, collecting the water formed in a Dean and Starkseparator. The cooled reaction mixture was then treated with excesssolid potassium carbonate and diluted with ether and water. The organiclayer was washed repeatedly with water until neutral, dried over sodiumsulphate and evaporated to dryness. Two crystallisations of the residuefrom methanol containing a trace of pyridine gavel6a-ethyl-3,G-acetoxy-pregn 5 en-20-one-ethylene-dioxyketal (16.5 g.).

The 3,8-acetoxy-pregn-5-en-20-one ZO-ethylenedioxyketal (13 g.) wasdissolved in a 0.3 N solution of potassium carbonate in 99.5% methanolcc.) and refluxed for 20 minutes. Addition of water to the cooledsolution gave l6oz-ethyl-pregm5-en-3B-ol-20-one 20-ethylenedioxyketal(11.5 g.).

ethyl pregn 5 en 3B 01 20 one 20 ethy-lenedioxyketal (18 g.) wasdissolved in toluene cc.) and cyclohexanone (90 cc.) and the solutionslowly distilled until free from water. The hot solution was thentreated with a solution of aluminium isopropoxide 10 g.) in toluene (20cc.), added over five minutes, and then heated to boiling with slowdistillation for 30 minutes. The cooled solution was treated with asolution of Rochelle salt (30 g.) in water and then steam distilleduntil free from steam volatile products. The crude solid was filtered,washed thoroughly with water and dried. Crystallisation from methanolcontaining a trace of pyridine gave l6d-ethyl-pregn-4-ene-3,20-dione20-ethylenedioxyketal (12.5 g.).

16d ethyl pregn 4 en 3,20 dione 20 ethylenedioxyketal (6.35 g.) wassuspended in methanol cc.) containing a few drops of pyridine. Sodiumborohydride (1.5 g.) was then added gradually over 1 hour with stirringat 20 C. andsolution was complete in about 10 minutes. The solution wasstirred for a further 2 hours at 20 C. and careful addition of watergave 16x-ethyl-pregn-4- en-3f3-ol-20-one 20-ethylenedioxyketal (6.35 g.)which could be crystallised from methanol. The acetate was prepared byreaction with acetic anhydride in pyridine overnight at 20 C.

16a-ethyl-pregn 4 en 35 ol-20-one ZO-ethylenedioxyketal (12 g.) wasdissolved in acetic acid (300 cc.) and the solution cooled to 25-30 C.Careful addition of water, dropwise at first, over 15 minutes andfinally complete watering out gave a gum which was extracted with etherand the ether solution washed to neutrality with sodium carbonatesolution and finally water. Evaporation of the dried extract gave an oilwhich crystallised from hexane/ acetone to give16a-ethyl-pregn-4-en-3[3-ol-20-one (7.5 g.).

The B d-acetate was prepared by reaction with acetic anhydride inpyridine overnight at 20 C.

The 35-hemisuccinate was prepared by dissolving the hydroxy compound (2g.) and recrystallised succinic anhydride (2.9 g.) in pyridine (20 cc.)and allowing the solution to stand at 20 C. for 19 days. The solutionwas then poured on to ice and acidified with 2 N HCl. The filtered,washed and dried product was crystallised from ether/hexane to give the3B-hemisuccinate (2.09 g.).

In an analogous manner the corresponding 3-esters derived fromisocaproic acid, oenanthic acid, S-phenyl propionic acid and lauric acidwere prepared.

EXAMPLE II 1604 isopropyl pregn 4 en 205 o1 3 one (2.6 g.) was dissolvedin pyridine (10 cc.) and the solution treated with propionic anhydridecc.). After standing at 20 C. for 18 hours ice was added and the solidfiltered, washed and dried to give the 20fi-propionate (2.8 g.) whichcould be crystallised from methanol. The finely divided propionate (2.5g.) was added to cold methanol (100 cc.) and the stirred suspensiontreated with sodium borohydride (650 mg.) added gradually over 1 hour.Solution was complete in about 30 minutes, and stirring was continuedfor a total of 3 hours, after which excess reagent was decomposed bycareful addition of acetic acid (5 cc.). Excess water was then added andthe solid filtered, washed and dried and crystallised from methanol togive 16u-isopropyl-pregn-4-ene-3,B,20fl-diol 20B-propionate (2.1 g.).Acetylation overnight in pyridine/ acetic anhydride and crystallisationof the watered out product from methanol gave16ot-isopropyl-pregn-4-ene-3,8,20,8-diol 3/3-acetate ZOB-propionate.

In the same manner the corresponding 3,8-acetate-20i3- oenanthate, and3fi-propionate-20fl-decanoate were prepared.

EXAMPLE III 16ot-methyl-pregn-4-en-3,B-ol-20-one g.) prepared in themanner as described in Example I was dissolved in pyridine and treatedwith propionic anhydride in the usual way and the product crystallisedfrom methanol to give the 3fl-propionate ('10 g.). The propionate (10g.) was dissolved in methanol (400 cc.) and the cooled solution wasstirred and treated portionwise with sodium borohydride (3.5 g.) keepingthe temperature below 20 C. After stirring for a total of 3 hours,excess borohydride was decomposed by careful addition of acetic acidcc.) and the product isolated in the usual way by addition of excesswater. Several crystallisations from aqueous methanol gave16a-methyl-pregn-4-ene-3{3,205-diol 3B-propionate (6 g.). Acetylation inpyridine/ acetic anhydride at C. for 16 hours and crystallisation of theproduct from methanol gave 16tx-methyl-pregn-4-en-3[3,20,8-diol3B-propionate ZOB-acetate.

In the same Way 16a-methyl-pregn-4-en-3[3,205-diol-3flphenyl propionateZOB-valerate was prepared.

EXAMPLE IV A solution of 16a-ethyl progesterone (20 g.; 0.0584

mole) in tetrahydrofuran cc.) was slowly stirred with a suspension ofsodium borohydride (825 mg; 0.0218 mole), at 1820 C. and the ultravioletabsorption of the reaction mixture was examined at intervals. After 48hours the ultraviolet absorption showed complete reduction of the3-ketone and the solution was cooled to 10 C. and excess borohydridedecomposed by dropwise addition of acetic acid (5 cc.). Careful additionof water gave a solid which was filtered, dried and crystallized fromhexane/acetone to give 16u-ethyl pregn-4-en-3B-ol-20-one (12.5 g.)containing approximately 10% of 16OL-ethyl-50tpregnan-3fl-ol-20-one.This mixture was purified by acetylation in acetic anhydride/pyridineovernight at 20 C. and the acetylated product was crystallised fromether/ hexane to give 16a-ethyl pregn-4-ene-3fl-ol-20-0ne acetate (9g.). The acetate was hy-drolised in aqueous methanolic potassiumcarbonate to giv 16'a-ethyl pregn-4-en-3,B-ol- 20-one (7.6 g.).

EXAMPLE V A solution of 16a-ethyl progesterone (1 g.) in tetrahydrofuran(8 cc.) was treated with sodium borohydride (42 mg.) and the solutionrefluxed gently until the ultraviolet absorption of the solution showedthat all the 3-ketone had been reduced. After 3 hours reflux thesolution was cooled to 1015 C. and excess borohydride decomposed withacetic acid. Careful addition of water gave a .solid (1 g.) which waspurified via the acetate as described in Example IV to give 16a-ethylpregn-4-ene-3fiol-20-one (380 mg).

EXAMPLE VI 16a-butyl progesterone (1.05 g.) in isopro-panol (25 cc.) wastreated with sodium borohyride (42 mg.) and the solution allowed tostand at 18-20 C. for 23 hours, by which time the ultraviolet absorptionof the solution showed that all the 3-ketone had been reduced. Thecooled solution was then treated with acetic acid (0.5 cc.) and carefuladdition of water gave a tacky solid which was p-rified via the acetateas described in Example IV to give 16u-butyl pregn-4-en-3/3-ol-20-one(369 mg).

EXAMPLE VII 1.63 g. of 16a-isopropyl pregna-4,6-diene-3,20-dione wasadded to a solution of lithium tri-t-butoxy aluminum hydride (600 mg;1.2 mole equivalents) in tetrahydrofuran (25 cc.). The solution was keptat 5 C. until the ultraviolet absorption of the reaction mixture showedthat the 3-ketone was completely reduced. After 50 hours excess reagentwas decomposed by careful addition of acetone and addition of water thengave a precipitate of crude product which 'was collected by filtration.Several recrystallisations from ether/ hexane gave 16x-isopropyl pregna-4,6-diene-3{i-ol-20-one (850 mg.).Acetylation of this compound withacetic anhydride in pyridine yielded the corresponding 3-acetate.

In the same manner a number of other 3-esters were prepared derived fromvaleric acid, oenanthic acid, 13- phenyl propionic acid and succinicacid.

EXAMPLE VIII A solution of 16a-ethyl pregna-4,6-diene-3,20-dione (5 g.)in tetrahy drofuran (30 cc.) was slowly stirred with a suspension ofsodium borohydride (230 mg.) at l820 C. until after 40 hours, theultraviolet absorption of the reaction mixture showed that the 3-ketonewas completely reduced. The solution was cooled to 10 C. and excessborohydride was decomposed by the addition of acetone. Careful additionof water gave a solid which was filtered, washed and dried andacetylated in pyridine (15 cc.) acetic anhydride (7.5 cc.). The productcrystallised from ether/hexane to give 16a-ethylpregn-4,6-diene-3fl-ol-20- one acetate (2.15 g.). The acetate washydrolysed in aqueous methanolic potassium carbonate to give 16a-ethylpregna 4,6 diene 3B ol 20 one (1.7 g.); k 233 (e=24,100), 239 26,950),248 (e='l8,000).

EXAMPLE 1X In a manner similar to Example VIII, 16a-etl1yl pregna-4,6-dien-3-one-20,B-ol ZO'acetate was reduced to 16a-ethylpregna-4,6-diene-3B-20fl-diol 20-acetate. The diacetate of the crudeproduct was recrystallized from ether/hexane and after hydrolysisyielded pure l6u-ethyl pregna-4,6- diene-3p,20p-dio1.

EXAMPLE X 16u-ethyl pregnenolone acetate g.) in petroleum ether, B.P.60-80 C. 100 ml.), was treated with collidine (2 ml.) followed byN-bromosuccinimide (5.26 g.; 1.14 mole equivalents) and refluxed for 30minutes in a flask protected from light. Filtration of the hot mixtureand exaporation under reduced pressure gave a gel which was treated withboiling collidine (50 ml.) and refluxed for 20 minutes. On cooling,ether (500 ml.) was added and the resulting solution Washed six timeswith 5 N hydrochloric acid (50 ml), then washed with water and driedover sodium sulphate. The ether solution was poured through a shortcolumn of alumina and the column eluted with a further 500 ml. ether.Evaporation of the ether gave 160:- ethyl pregna-4,6-diene-3,8-ol-20-oneacetate which was dissolved in a saturated solution of potassiumcarbonate in methanol (100 ml.) and left overnight at room temperature.Careful addition of water and crystallisation of the product fromacetone gave l6a-ethyl pregna-4,6-diene- 3B-ol-20-one (0.78 g.), A 233(e=23,400), 239 (e=26,350), 248 (e=17,100).

In the way as described in Example I this compound was converted intothe corresponding 3-esters derived from Valerie acid, capric acid,.succinic acid and fl-phenyl propionic acid.

We claim:

1. A steroid compound of the formula: (3H3 I C=R3 6 wherein R issaturated hydrocarbon having 1-4 carbon atoms,

R is selected from the group consisting of hydrogen and acyl derivedfrom a member of the group consisting of an inorganic acid and anorganic acid having 1 to 18 carbon atoms,

R is selected from the group consisting of a keto group,

H(OH) and H(OAcyl) wherein acyl is derived from a member of the groupconsisting of an inorganic acid and an organic acid having 1 to 18carbon atoms, and

C -C is selected from the group consisting of a saturated andunsaturated bond, and when C -C is an unsautrated bond and R is selectedfrom the group consisting of H(OH) and H(OAcyl), R is ethyl, and when C-C is a saturated bond and R is a keto group, R is also ethyl.

2. A compound selected from the group consisting of A-3fl-hydroxy-16a-ethyl-20-keto-pregnene and the corresponding3-acylates, the acyl of which is derived from a member of the groupconsisting of an inorganic acid and an organic acid having 1 to 18carbon atoms.

3. A compound selected from the group consisting of a A-3fi-hydroxy-16ot-lower alkyl-ZO-keto-pregnadiene and the corresponding3acylates, the acyl of which is derived from a member of the groupconsisting of an inorganic acid and an organic acid having 1 to 18carbon atoms.

4. A compound selected from the group consisting of A 3,8hydroxy-16a-e'thyl-20-keto-pregnadiene and the corresponding 3-acylates,the acyl of which is derived from a member of the group consisting of aninorganic acid and an organic acid having 1 to 18 carbon atoms.

OTHER REFERENCES Marker et al.: Journal American Chem. Soc., vol. 64(1942), pages 12801281 relied on.

Methods in Hormone Research,

vol. II (1962), pages 148149 relied on. Academic Press:

Inc., New York.

ELBERT L. ROBERTS, Primary Examiner. LEWIS GOTTS, Assistant Examiner.

1. A STEROID COMPOUND OF THE FORMULA: